Nicotine is self-administered via cigarette smoking by the great majority of patients with schizophrenia. Nicotine has direct effects on cognitive function and interacts with antipsychotic drugs to substantially influence their actions on cognitive function. The cognitive effects of nicotine may present a novel opportunity for improving the treatment of cognitive dysfunction associated with schizophrenia and cognitive dysfunction induced by antipsychotic drugs. Classical neuroleptics such as haloperidol and "atypical" antipsychotics such a clozapine and risperidone have substantially different mechanisms of action and likely interact with nicotine in quite different ways. The proposed project will determine the functional mechanisms by which nicotinic systems interact with antipsychotic drugs to affect cognitive function. Both classical and atypical antipsychotic drugs have been found to impair memory function. Haloperidol-induced working memory deficits have been found in our earlier studies of schizophrenic patients and laboratory rats to be reversed by acute doses of nicotine. Recently, we have found that the working memory impairment caused in rats by clozapine administration can be reversed by nicotine. These effects will be used as a forum in which to determine the critical neural mechanisms by which nicotine interacts with antipsychotic drugs in the control of memory function. We hypothesize that nicotinic receptor systems in the hippocampus are a key mechanism by which nicotine alleviates schizophrenia associated attentional impairment and antipsychotic drug-induced memory impairment. Nicotinic innervation of the hippocampus has been found in our previous studies to be critical for nicotine effects on memory. Importantly, we have also shown that hippocampal DA innervation is also important for memory function. The proposed project will specify the mechanisms underlying nicotinic interactions with antipsychotic effects on memory function, including involvement of nicotinic receptor subtypes and their anatomic loci in hippocampus important for memory function. Dose response local infusion studies with selective nicotinic antagonist subtypes will be used to determine the relationship of nicotinic systems for memory performance in the benchmark radial-arm maze task as well as an operant attention task. These basic studies will help elucidate important therapeutic issues concerning the impact of nicotinic co- treatment with classic and atypical antipsychotic drugs to improve memory and attentional function. These studies will provide information concerning neural systems likely to underlie nicotinic actions we have seen on a systemic level and facilitate the development of new drug therapies for cognitive dysfunction in schizophrenia.